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Dosing for CABOMETYX® (cabozantinib) with OPDIVO® (nivolumab)

Dosing for CABOMETYX® (cabozantinib) with OPDIVO® (nivolumab)

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CABOMETYX 40-mg, once-daily starting dose—optimized for combination treatment with OPDIVO1

Optimized dosing for CABOMETYX® (cabozantinib) when used in combination with OPDIVO is a single 40-mg pill taken once daily

Treatment with CABOMETYX should be continued until disease progression or unacceptable toxicity. 
Treatment with OPDIVO should be continued until disease progression or unacceptable toxicity for up to 2 years.

Recommended administration of CABOMETYX1

DO NOT ADMINISTER CABOMETYX WITH FOOD

Administer CABOMETYX at least 1 hour before or at least 2 hours after eating

Swallow CABOMETYX tablet whole

DO NOT CRUSH

  • Withhold CABOMETYX for at least 3 weeks prior to elective surgery, including dental surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed
  • DO NOT substitute CABOMETYX tablets with cabozantinib capsules
  • Modify the dosage for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP3A4
  • When administering CABOMETYX in combination with OPDIVO for the treatment of aRCC, refer to the OPDIVO Prescribing Information

Advise patients of the following, if a dose is missed and the next scheduled dose is:

in less than 12 hours       
  • DO NOT make up the missed dose
  • Take the next dose at the usual time
in 12 hours or more      
  • Talk to their doctor or nurse

Pharmacokinetics

  • The predicted terminal half-life of CABOMETYX is approximately 99 hours
Download Dosing and Administration Guide

CABOMETYX is a 1-tablet dose even if dose adjustments are needed1

Withhold CABOMETYX for intolerable Grade 2 ARs, Grade 3 ARs, and ONJ. Upon resolution/improvement (ie, return to baseline or resolution to Grade 1) of an AR, reduce the dosage based on the chart below.

Combination 
starting dosage

First reduction

Second reduction

Cabometyx 40mg pill 
40 mg 
once daily

Cabometyx 20mg pill 
20 mg 
once daily

Cabometyx 20mg pill 
20 mg 
once every other day*

Combination
starting dosage

Cabometyx 40mg pill40 mg once daily

First
reduction

Cabometyx 20mg pill20 mg once daily

Second 
reduction

Cabometyx 20mg pill20 mg once every other day*

Tablets shown are not actual size.

*

If previously receiving 20 mg once every other day, resume at same dose. If not tolerated, discontinue CABOMETYX.

Of the patients who needed to reduce their dosage, most required only 1 dose reduction2

20 mg once daily 20 mg once every other day
50.3% 8.1%

The mean average daily dose of CABOMETYX was 30 mg/day2

Primary analysis: Discontinuation rate due to ARs for CABOMETYX + OPDIVO was 6%1

 

Permanent discontinuation

Dose interruption/reduction

CABOMETYX or OPDIVO

20%

83%

CABOMETYX only

8%

46%

OPDIVO only

7%

3%

CABOMETYX and OPDIVO

6%†

21%‡ 

sunitinib3

16.9%

72.5%

†

Due to the same AR at the same time.

‡

Due to the same AR at the same time; 6% for both drugs sequentially.

8%

The discontinuation rate of CABOMETYX alone was 8%1

  • Permanently discontinue CABOMETYX for Grade 3 or 4 hemorrhage, development of a GI perforation or Grade 4 fistula, acute myocardial infarction or Grade 2 or higher cerebral infarction, Grade 3 or 4 arterial thromboembolic events or Grade 4 venous thromboembolic events, Grade 4 hypertension/hypertensive crisis or Grade 3 hypertension/hypertensive crisis that cannot be controlled, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome1

For patients being treated with CABOMETYX in combination with OPDIVO1:

  • If ALT or AST >3x ULN but ≤10x ULN without concurrent total bilirubin ≥2x ULN, both CABOMETYX and OPDIVO should be withheld until hepatic ARs recover to Grades 0 or 1. Corticosteroid therapy may be considered. Rechallenge with a single medicine or rechallenge with both medicines after recovery may be considered. If rechallenging with OPDIVO, refer to OPDIVO Prescribing Information
  • If ALT or AST >10x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN, both CABOMETYX and OPDIVO should be permanently discontinued

 

When strong CYP3A4 inhibitors cannot be avoided1

CABOMETYX® (cabozantinib) + OPDIVO® (nivolumab) dose reduction

Reduce the daily dose of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided.

Resume CABOMETYX at the dose that was used prior to initiating the strong CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

Examples of strong CYP3A4 inhibitors§:
  • Boceprevir
  • Clarithromycin
  • Conivaptan
  • Grapefruit juice
  • Indinavir/ritonavir
  • Itraconazole
  • Ketoconazole
  • Lopinavir/ritonavir 
  • Nefazodone
  • Nelfinavir
  • Posaconazole
  • Ritonavir
  • Saquinavir/ritonavir
  • Voriconazole

 

When strong CYP3A4 inducers cannot be avoided1

CABOMETYX® (cabozantinib) + OPDIVO® (nivolumab) dose increase

Increase the daily dose of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

For example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily, as tolerated

  • Do not exceed a daily dose of 80 mg

Resume CABOMETYX at the dose that was used prior to initiating the strong CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.

Examples of strong CYP3A4 inducers§:
  • Rifampin
  • Phenytoin
  • Carbamazepine
  • St. John’s wort
§

Examples listed may not be comprehensive.

See Exploratory Quality of Life Data
Downloadable Cabometyx dosing guide

Download the CABOMETYX Dosing and Administration Guide

Download
Downloadable Cabometyx dosing guide

Download the CABOMETYX Treatment Management Guide

Download
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ALT=alanine aminotransferase; AR=adverse reaction; aRCC=advanced renal cell carcinoma; AST=aspartate aminotransferase; CYP3A4=cytochrome P450 3A4; GI=gastrointestinal; IV=intravenous; ONJ=osteonecrosis of the jaw; RCC=renal cell carcinoma; ULN=upper limit of normal.

References:

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
  2. Data on file. Exelixis, Inc.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see full Prescribing Information.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Indication

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

OPDIVO® and the related logo are registered trademarks of Bristol-Myers Squibb Company.

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